Previously, we have demonstrated that infection of monocytes with HIV is associated with increased expression of b2 integrins, which increases both monocyte aggregation and monocyte/endothelial adhesion as well as monocyte metalloproteinase (MMP-9) expression. These altered biological function of HIV-infected monocytes may contribute to rapid extravasation of infected monocytes from vasculature into tissues for the spread of HIV disease. We have extended this observation to examine the mechanism by which HIV infection alters monocyte function. We have demonstrated that treatment of monocytes with HIV-tat protein, a product of a viral regulatory gene Tat that transactivates the HIV-LTR promoter and is secreted by HIV-infected cells, mimics many of the properties of HIV-infected monocytes. Tat treatment upregulated the expression of the b2 integrins on monocytes. The increased expression of adhesion molecules was associated with the formation of large aggregates of monocytes and their increased adhesion to both rested and TNF-a-activated microvascular endothelial cells. The increased adhesion of tat-treated monocytes was accompanied by substantial disruption of the endothelial monolayers, with retraction or detachment of individual endothelial monolayers. Furthermore, tat treatment of monocytes upregulated the synthesis and release of protease MMP-9, which provides a potential mechanism to explain endothelial cell/basement membrane detachment. Thus, extracellular tat is capable of activating monocytes even in the absence of HIV infection. These results suggest a mechanism where monocytes could be inappropriately activated by HIV-tat, secreted by HIV-infected cells, causing them to extravasate into underlying tissues and ultimately contribute to tissue damage as seen during the progression of AIDS. In another study, we have identified a new subpopulation of monocytes that lacks CD14 surface phenotype. We have further demonstrated that HIV productively infects and alters immune function of monocyte subsets. One manuscript describing this work is published in the Journal of Immunology 154:422, 1995, and two others have been submitted for publication. Further studies are in progress to identify viral and cellular factors involved in HIV pathogenesis at various stage of HIV infection of monocytes. These studies may not only enhance our basic understanding of HIV infection, but may also provide information to develop strategies for the detection of HIV, especially in the early stage of the disease.